Aclidinium for use in improving the quality of sleep in respiratory patents

ABSTRACT

The present invention provides aclidinium or any of its steroisomers or mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for improving the quality of sleep in respiratory patients.

FIELD OF THE INVENTION

The invention relates to a novel use of aclidinium, which can beadvantageously used to improve the quality of sleep in respiratorypatients.

BACKGROUND OF THE INVENTION

Respiratory diseases, such as asthma and chronic obstructive pulmonarydisease (COPD), are a significant global health program, with anincreasing incidence throughout the world. They are usuallycharacterised by an inflammatory dysfunction of the airways whichresults in bronchoconstriction.

In asthma inflammation is driven by exposure to a variety of triggers,including allergens and viruses, which activate components of both theinnate and acquired immune responses. In COPD inflammation occursprimarily because of exposure to noxious particles and gases, inparticular to cigarette smoke. Rather than a single pathologiccondition, COPD is a term encompassing several disorders, such aschronic bronchitis or emphysema.

Asthma and COPD are commonly associated with severe impairment of thephysical functions as a consequence of pulmonary symptoms such asdyspnoea (breathlessness), fatigue, cough, wheezing, chest tightness orcongestion, and sputum production. Many patients with respiratorydiseases complain of the serious impact of these symptoms in the qualityof their sleep.

In COPD patients, sleep-related complaints are the third most commonlyreported symptoms, after dyspnoea and fatigue (Kinsman et al, Chest,1983, 83, 755-761). In the case of asthma, 80% of the patients are wokenat least occasionally by nocturnal wheeze and cough, and many patientswith severe stable asthma are woken virtually every night(Turner-Warwick, M.; Am. J. Med., 1988, 85 (suppl. 1B), 6-8).

Sleep complaints frequently reported by respiratory patients are forexample longer latency to falling asleep, difficulty in staying asleep,frequent arousals and awakenings, superficial sleep, reduction of totalsleep time, waking up too early and not being able to get back to sleep,generalised insomnia and, overall, a much poorer quality of sleep.Excessive daytime sleepiness and restricted physical activity during theday due to breathlessness in the morning are also common consequences ofthe impaired quality of sleep.

These sleep disturbances tend to be more severe with advancing diseaseand substantially reduce the quality of life of respiratory patients.

Bronchodilating agents like the beta-adrenergic agonists or theantagonists of cholinergic muscarinic receptors (commonly known asanticholinergics or antimuscarinics) are usually prescribed forinhalation to respiratory patients suffering from obstructive airwaydiseases, such as asthma or COPD. All commercially availableanticholinergics are synthetic tropane derivatives, and includeipratropium, oxitropium, and tiotropium. Tiotropium, is the onlylong-acting anticholinergic currently on the market.

It is well known that the impact of the circadian rhythm on airwayresponsiveness and airway resistance is much larger in respiratorypatients that in normal subjects. As a consequence, respiratory patientsare particularly prone to bronchoconstriction at night and in the earlymorning hours and this is the main factor affecting the quality of theirsleep. Therefore, a treatment aimed at overcoming or preventingbronchoconstriction during the night is highly desirable. However, astudy by Calverley et al., in Thorax, 2003, 58 (10), 855-860 shows thatthe administration of the long-acting bronchodilator tiotropium in theevening does not produce more bronchodilation during the night than whenit is administered only in the morning.

It has now surprisingly been found that aclidinium significantlydiminishes the occurrence of the sleep disturbances commonly seen inrespiratory patients, increasing thus quality of sleep and overallquality of life.

Aclidinium is3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, a long-acting muscarinic receptor antagonist in development byAlmirall for administration by inhalation in the treatment ofrespiratory diseases, especially asthma and COPD. It was first disclosedin WO 01/04118.

Aclidinium is rapidly hydrolysed in human plasma to two inactivemetabolites, and hence has a reduced potential for systemic side effectsand a wider safety margin than currently available inhaledanticholinergic treatments. Its additional effect in improving qualityof sleep is an unexpected finding of this invention.

SUMMARY OF THE INVENTION

The present invention provides aclidinium, or any of its steroisomers ormixture of stereoisomers, or a pharmaceutically acceptable salt orsolvate thereof, for use in improving the quality of sleep inrespiratory patients.

Preferably, aclidinium is in the form of a salt with an anion X⁻. Mostpreferably, the anion X⁻ is bromide.

In a preferred embodiment, the respiratory patient suffers from adisease selected from acute or chronic bronchitis, emphysema, asthma andchronic obstructive pulmonary disease, preferably asthma and chronicobstructive pulmonary disease, most preferably chronic obstructivepulmonary disease.

In another embodiment, aclidinium is administered as a pharmaceuticalcomposition suitable for inhalation, preferably in the form of a drypowder. The composition can be administered by means of any inhalerdevice, more preferably the Genuair®.

Typically, a dry powder formulation comprises a pharmaceuticallyacceptable carrier selected from mono-, di- or polysaccharides and sugaralcohols. Preferably, the carrier is lactose.

Aclidinium is administered at least once a day, preferably in themorning or in the evening. More preferably aclidinium is administeredtwice daily. In a most preferred embodiment aclidinium is administeredtwice daily, one in the morning and another one in the evening.

The effective dose of aclidinium to be used per inhalation is theequivalent to a metered nominal dose from 100 to 1000 micrograms ofaclidinium bromide in a dry powder for inhalation, more preferably 200or 400 micrograms of aclidinium bromide.

In another preferred embodiment, aclidinium is co-administered with anadditional medication suitable for the treatment of respiratorydiseases, selected for example from one or more of the following:corticosteroids, beta-adrenergic agonists, PDE4 inhibitors,antihistamines, anti-IgE antibodies, leukotriene D4 inhibitors,inhibitors of egfr-kinase, p38 kinase inhibitors and/or NK1-receptorantagonists. The additional medications can be present in the samepharmaceutical composition as aclidinium or in separate pharmaceuticalcompositions. Preferably, the additional medication is selected fromcorticosteroids, beta-adrenergic agonists and/or PDE4 inhibitors.

The improvement by aclidinium of the quality of sleep of the respiratorypatient can be measured by observing the reduction of one or more of thefollowing:

-   a) Latency to falling asleep-   b) Total number of awakenings-   b) Early awakenings-   c) Difficulty in staying asleep-   d) Superficial sleep-   e) Insomnia-   f) Daytime sleepiness or fatigue-   g) Restriction of activities during the morning    and/or by the increase of total sleep time.

Among the clinical factors that may contribute to the improvement of thequality of sleep by aclidinium are reductions in one or more of thefollowing respiratory complaints during sleep time:

-   a) Cough severity and/or frequency-   b) Sputum production-   c) Wheezing-   d) Chest tightness-   e) Chest congestion-   f) Bronchoconstriction-   g) Breathlessness-   h) Need of rescue medication

The invention further provides a pharmaceutical composition comprisingaclidinium for improving the quality of sleep in respiratory patients.

The invention further provides the use of aclidinium in the manufactureof a medicament for improving the quality of sleep in respiratorypatients.

The invention further provides a method of improving the quality ofsleep in respiratory patients, which method comprises administering tosaid patient an effective amount of aclidinium, as defined above.

DETAILED DESCRIPTION OF THE INVENTION

Typically, the aclidinium is administered in the form of a salt with ananion X⁻, wherein X⁻ is a pharmaceutically acceptable anion of a mono orpolyvalent acid. More typically, X⁻ is an anion derived from aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulphuricacid and phosphoric acid, or an organic acid such as methanesulphonicacid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acidor maleic acid. Most preferably the aclidinium is in the form ofaclidinium bromide.

The compound of the invention may exist in both unsolvated and solvatedforms. The term solvate is used herein to describe a molecular complexcomprising a compound of the invention and an amount of one or morepharmaceutically acceptable solvent molecules. The term hydrate isemployed when said solvent is water. Examples of solvate forms include,but are not limited to, compounds of the invention in association withwater, acetone, dichloromethane, 2-propanol, ethanol, methanol,dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, ormixtures thereof. It is specifically contemplated that in the presentinvention one solvent molecule can be associated with one molecule ofthe compounds of the present invention, such as a hydrate.

The words “treatment” and “treating” are to be understood as embracingamelioration of symptoms of a disease or condition and/or elimination orreduction of the cause of the disease or condition and/or prevention ofthe appearance of the disease or its symptoms.

The term “therapeutically effective amount” refers to an amountsufficient to effect treatment when administered to a patient in need oftreatment.

Aclidinium can also be used in combination with other drugs known to beeffective in the treatment of the diseases or the disorders indicatedabove. For example aclidinium can be combined with corticosteroids orglucocorticoids, beta-adrenergic agonists, PDE4 inhibitors,antihistamines, anti-IGE antibodies, leukotriene D4 antagonists,inhibitors of egfr kinase, p38 kinase inhibitors and/or NK-1 receptoragonists.

Corticosteroids that can be combined with aclidinium in the presentinvention particularly include those suitable for administration byinhalation in the treatment of respiratory diseases or conditions, e.g.,prednisolone, methylprednisolone, dexamethasone, naflocort, deflazacort,halopredone acetate, budesonide, beclomethasone dipropionate,hydrocortisone, triamcinolone acetonide, fluocinolone acetonide,fluocinonide, clocortolone pivalate, methylprednisolone aceponate,dexamethasone palmitoate, tipredane, hydrocortisone aceponate,prednicarbate, alclometasone dipropionate, halometasone,methylprednisolone suleptanate, mometasone furoate, rimexolone,prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasonepropionate, halobetasol propionate, loteprednol etabonate, betamethasonebutyrate propionate, flunisolide, prednisone, dexamethasone sodiumphosphate, triamcinolone, betamethasone 17-valerate, betamethasone,betamethasone dipropionate, hydrocortisone acetate, hydrocortisonesodium succinate, prednisolone sodium phosphate and hydrocortisoneprobutate. Budesonide and mometasone are especially preferred.

Beta-adrenergic agonists that can be combined with aclidinium in thepresent invention particularly include (32 adrenergic agonists usefulfor treatment of respiratory diseases or conditions, for example,selected from the group consisting of arformoterol, bambuterol,bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol,formoterol, hexoprenaline, ibuterol, isoprenaline, mabuterol,meluadrine, nolomirole, orciprenaline, pirbuterol, procaterol,reproterol, ritodrine, rimoterol, salbutamol, salmeterol, sibenadet,sulfonterol, terbutaline, tulobuterol, vilanterol, olodaterol, KUL-1248,LAS-100977, carmoterol and indacaterol, in free or pharmaceuticallyacceptable salt form. Preferably, the (32 adrenergic agonist is along-acting (32 adrenergic agonist, e.g., selected from the groupconsisting of formoterol, salmeterol, carmoterol , vilanterol,olodaterol, LAS-100977 and indacaterol in free or pharmaceuticallyacceptable salt form.

PDE4 inhibitors that can be combined with aclidinium in the presentinvention include denbufylline, rolipram, cipamfylline, arofylline,filaminast, piclamilast, mesopram, drotaverine hydrochloride,lirimilast, roflumilast, cilomilast,6-[2(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid,(R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine,N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide,9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine,N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide,N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide,3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purinehydrochloride,4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluroromethoxyphenyl)cyclohexanl-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol,ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and the compoundsclaimed in the PCT patent application number WO03/097613, andPCT/EP03/14722 and in the Spanish patent application numer P200302613.

Aclidinium for use in the present invention may be administered by anysuitable route to provide local antimuscarinic action. It is preferablyadministered by inhalation, e.g., as a powder, spray, or aerosol,preferably as a dry powder. Pharmaceutical compositions comprisingaclidinium may be prepared using conventional diluents or excipients andtechniques known in the galenic art.

Medicaments for administration in a dry powder for inhalation desirablyhave a controlled particle size. The optimum particle size forinhalation into the bronchial system is usually 1-10 nm, preferably 2-5nm. Particles having a size above 20 nm are generally too large wheninhaled to reach the small airways. To achieve these particle sizes theparticles of the active ingredient as produced may be size reduced byconventional means, e.g. by micronisation or supercritical fluidtechniques. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline.

Achieving a high dose reproducibility with micronised powders isdifficult because of their poor flowability and extreme agglomerationtendency. To improve the efficiency of dry powder compositions, theparticles should be large while in the inhaler, but small whendischarged into the respiratory tract. Thus, an excipient, for example amono-, di- or polysaccharide or sugar alcohol, such as lactose, mannitolor glucose is generally employed. The particle size of the excipientwill usually be much greater than the inhaled medicament within thepresent invention. When the excipient is lactose it will typically bepresent as lactose particles, preferably crystalline alpha lactosemonohydrate, e.g., having an average particle size range of 20-1000 μm,preferably in the range of 90-150 μm. In one embodiment, the lactoseparticles for use in formulations of the invention have a d10 of 90-160μm, a d50 of 170-270 μm, and d90 of 290-400 μm.

Suitable lactose materials for use in the present invention arecommercially available, e.g., from DMW Internacional (Respitose GR-001,Respitose SV-001, Respitose SV-003); Meggle (Capsulac 60, Inhalac 70,Capsulac 60 INH); and Borculo Domo (Lactohale 100-200, Lactohale200-300, and Lactohale 100-300).

The ratio between the lactose particles and the aclidinium by weightwill depend on the inhaler device used, but is typically, e.g., 5:1 to200:1, for example 50:1 to 150:1, e.g., 60-70:1.

In a preferred embodiment, the aclidinium is administered in the form ofa dry powder formulation of aclidinium bromide in admixture withlactose, in a ratio by weight of aclidinium to lactose of 1:50 to 1:150,suitable for administration via a dry powder inhaler, wherein theaclidinium particles have an average particle size of from 2 to 5 μm indiameter, e.g., less than 3 μm in diameter, and the lactose particleshave a d10 of 90-160 μm, a d50 of 170-270 μm, and d90 of 290-400 μm.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine or blisters of for example laminated aluminium foil, for use inan inhaler or insufflator. Each capsule or cartridge may generallycontain between 0.001-50 mg, more preferably 0.01-5 mg of activeingredient or the equivalent amount of a pharmaceutically acceptablesalt thereof. Alternatively, the active ingredient (s) may be presentedwithout excipients.

Packaging of the formulation may be suitable for unit dose or multi-dosedelivery. In the case of multi-dose delivery, the formulation can bepre-metered or metered in use. Dry powder inhalers are thus classifiedinto three groups: (a) single dose, (b) multiple unit dose and (c) multidose devices.

Aclidinium is preferably administered with a multi-dose inhaler, morepreferably with the Genuair® (formerly known as Novolizer SD2FL), whichis described the following patent applications Nos: WO97/000703,WO03/000325 and WO2006/008027.

Dosages will vary depending on, e.g., the individual, the mode andfrequency of administration, and the nature and severity of thecondition to be treated. Daily dosages for a 70 kg adult human maytypically for example be on the order of 100-1000 micrograms of activeagent in the form of dry powder for inhalation.

EXAMPLE 1

In a Phase Ha randomized, double-blind, crossover trial, patients withmoderate to severe

COPD received aclidinium 400 micrograms twice-daily (in the morning, 9am, and in the evening, 9 pm) and placebo for 15 days, with a 9-15 daywashout between treatment periods.

Sleep quality was assessed with daily records on a patient diary cardusing a 0-4 score according to the following criteria:

0 No awakenings 1 Early awakening or awakening once during the night 2Early awakening or awakening two or more times during the night 3Awakening for most time during the night 4 The patient could not sleepat all

Patients treated with aclidinium showed a significantly improved qualityof sleep compared to untreated patients.

EXAMPLE 2

In a double-blind, randomised, placebo-controlled Phase III trial, thequality of sleep and the use of rescue medication was assessed duringtwice-daily treatment of aclidinium bromide in COPD patients.

COPD patients with FEV1/FVC<70% were randomised (1:1:1) to aclidinium200 micrograms, 400 micrograms, or placebo. The quality of sleep wasreported daily using electronic diaries and a questionnaire, whichassessed symptom frequency and severity and its effect on morningactivities. Rescue medication use was also assessed.

At Week 12, aclidinium significantly improved the quality of sleepcompared to placebo. Aclidinium 200 mcg and 400 mcg significantlyreduced the severity of breathlessness and cough at night, the frequencyof awakenings and the difficulty to fall back sleep. Additionally, theproduction of sputum and the use of rescue medication were also reduced.

Both aclidinium doses also significantly reduced the severity of earlymorning breathlessness and the impact of breathlessness and cough onmorning activities.

EXAMPLE 3

In a Phase Ha randomised, double-blind, double-dummy, crossover trial,patients with moderate-to-severe COPD received inhaled aclidinium 400 μgBID, tiotropium 18 μg QD and placebo for 15 days, with a 9-15 daywashout between treatment periods.

The incidence of sleep difficulties was recorded daily on a patientdiary card. As in Example 1, the scores ranged from 0 for none to 1-4for increasing severity of the sleep difficulties. The change in thescore produced by each treatment with respect to the baseline was thenmeasured.

The average score (±SEM) of the patients treated with tiotropium was−0.011 (0.091), which is practically identical to the baseline and verysimilar to the score of 0.061 (0.088), observed in the patients treatedwith placebo. There is no statistically significant difference betweenthese two scores (p>0.05). In contrast, the score of the patientstreated with aclidinium was −0.123 (0.089). In this case there is astatistically significant difference with placebo (p<0.05).

These phase Ha results demonstrate that the remarkable improvement ofsleep quality produced by aclidinium is not observed when the patientsare treated with tiotropium, the reference anticholinergic drugcurrently in the market. This unexpected effect of aclidinium istherefore not obvious and involves an inventive step.

1. A method for improving the quality of sleep in a patient in needthereof, comprising: administering to the patient a pharmaceuticalcomposition comprising aclidinium, its stereoisomers or mixture ofstereoisomers, or a pharmaceutically acceptable salt or solvate thereof.2. The method according to claim 1, wherein the aclidinium is in theform of aclidinium bromide.
 3. The method according to claim 1, whereinthe patient suffers from asthma or chronic obstructive pulmonarydisease.
 4. The method according to claim 1, wherein the aclidinium isin the form of a dry powder formulation suitable for inhalation.
 5. Themethod according to claim 4, wherein the formulation is administered ina dosage comprising an amount of aclidinium ranging from 100 microgramsto 1000 micrograms of aclidinium bromide per inhalation.
 6. The methodaccording to claim 1, wherein the composition comprising aclidinium isadministered at least once per day.
 7. The method according to claim 1,wherein the composition comprising aclidinium is administered with atherapeutically effective amount of at least one other medication chosenfrom corticosteroids, beta-adrenergic agonists, and PDE4 inhibitors. 8.The method according to claim 1, wherein the quality of sleep isimproved by reducing at least one of the following: a) Latency tofalling asleep, b) Total number of awakenings, b) Early awakenings, c)Difficulty in staying asleep, d) Superficial sleep, e) Insomnia, f)Daytime sleepiness or fatigue, g) Restriction of activities during themorning, and/or by increasing total sleep time,
 9. (canceled) 10.(canceled)
 11. The method according to claim 1, wherein thepharmaceutical composition comprises aclidinium in an effective amount.12. The method according to claim 1, wherein the patient suffers fromrespiratory disorder.
 13. (canceled)
 14. (canceled)
 15. The methodaccording to claim 12, wherein the impaired sleep involves at least oneof the following: a) delay in falling asleep, b) at least one awakeningduring the night, b) early awakenings, c) difficulty in staying asleep,d) superficial sleep, e) insomnia, f) daytime sleepiness or fatigue, org) restriction of activities during the morning.
 16. The methodaccording to claim 5, wherein the formulation is administered in adosage comprising an amount of aclidinium ranging from 200 micrograms to400 micrograms of aclidinium bromide per inhalation.
 17. The methodaccording to claim 5, wherein the dosage of aclidinium is 200 microgramsof aclidinium bromide per inhalation.
 18. The method according to claim5, wherein the dosage of aclidinium is 400 micrograms of aclidiniumbromide per inhalation.
 19. The method according to claim 6, wherein thecomposition comprising aclidinium is administered twice daily.
 20. Themethod according to claim 12, wherein the patient suffers from asthma orchronic obstructive pulmonary disease.
 21. The method according to claim15, wherein the impaired sleep involves at least one of the following:a) delay in falling asleep, b) at least two awakenings during the night,b) early awakenings, c) difficulty in staying asleep, d) superficialsleep, e) insomnia, f) daytime sleepiness or fatigue, or g) restrictionof activities during the morning.
 22. The method according to claim 15,wherein the impaired sleep involves at least one of the following: a)delay in falling asleep, b) at least three awakenings during the night,b) early awakenings, c) difficulty in staying asleep, d) superficialsleep, e) insomnia, f) daytime sleepiness or fatigue, or g) restrictionof activities during the morning.